The objective of this proposal is to continue a comprehensive research program focused on study of mechanisms of limbic epilepsy. The proposal brings together investigators with skills in molecular neurobiology, electrophysiology, anatomy, pharmacology, and clinical epilepsy. These skills will be focused on tests of alternative hypotheses advanced to explain the hyperexcitability of limbic epilepsy. These alternative hypotheses will be tested in a diversity of preparations including animal models in vivo as well as a diversity of reduced in vitro preparations, some of which have been isolated from the rodents in which epilepsy has been induced. The work is centered in particular on the excitability of two principal neuronal populations, the dentate granule cells and CA3 pyramidal cells. Successful completion of the work proposed promises to shed light on the mechanisms underlying limbic epilepsy. Such insights will hopefully lead to new and more effective therapies and perhaps prevent development of this disorder. Insights into normal hippocampal circuitry and how it is modified following brain injury and pathologic activity will also emerge from this work, this promises to aid understanding of a diversity of nervous system disorders in addition to limbic epilepsy.